ArticleScience signaling2015
Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17.
Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 60 citations in OpenAlex.
- Structural basis for ADAM17 activation by the iRhom1 pseudoprotease.Cell reports · 2026Article
- Progress of ADAM17 in Fibrosis-Related Diseases.Mediators of inflammation · 2025Review
- Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity.Cellular and molecular life sciences : CMLS · 2024Article
- Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.Molecular cell · 2024Article
- Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment.Current neuropharmacology · 2024Review
- Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice.Journal of cell science · 2023Article
- The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review.Oncogene · 2023Review
- Antiviral Potential of Small Molecules Cordycepin, Thymoquinone, and N6, N6-Dimethyladenosine Targeting SARS-CoV-2 Entry Protein ADAM17.Molecules (Basel, Switzerland) · 2022Article
- iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells.Journal of cell science · 2022Article
- Alternative splicing of the human rhomboid family-1 gene RHBDF1 inhibits epidermal growth factor receptor activation.The Journal of biological chemistry · 2022Article
- Review
- iRhom2: An Emerging Adaptor Regulating Immunity and Disease.International journal of molecular sciences · 2020Review
- ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1).The Journal of biological chemistry · 2020Article
- The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders.Frontiers in cardiovascular medicine · 2020Review
- Gene Expression of Metalloproteinases and Endogenous Inhibitors in the Lamellae of Dairy Heifers With Oligofructose-Induced Laminitis.Frontiers in veterinary science · 2020Article
- Review
- The emerging role of ADAM metalloproteinases in immunity.Nature reviews. Immunology · 2018Review
- Human rhomboid family-1 modulates clathrin coated vesicle-dependent pro-transforming growth factor α membrane trafficking to promote breast cancer progression.EBioMedicine · 2018Article
- iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE.eLife · 2018Article
- FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex.eLife · 2018Article
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Authors and funding
21 authors at 8 institutions in 4 countries.
Funding
Abstract
The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune response and promotes programmed cell death but can also promote sepsis. Catalytically inactive members of the rhomboid family of proteases, iRhom1 and iRhom2, mediate the intracellular transport and maturation of ADAM17. Using a genetic screen, we found that the presence of either iRhom1 or iRhom2 lacking part of their extended amino-terminal cytoplasmic domain (herein referred to as ΔN) increases ADAM17 activity, TNFR shedding, and resistance to TNF-induced cell death in fibrosarcoma cells. Inhibitors of ADAM17, but not of other ADAM family members, prevented the effects of iRhom-ΔN expression. iRhom1 and iRhom2 were functionally redundant, suggesting a conserved role for the iRhom amino termini. Cells from patients with a dominantly inherited cancer susceptibility syndrome called tylosis with esophageal cancer (TOC) have amino-terminal mutations in iRhom2. Keratinocytes from TOC patients exhibited increased TNFR1 shedding compared with cells from healthy donors. Our results explain how loss of the amino terminus in iRhom1 and iRhom2 impairs TNF signaling, despite enhancing ADAM17 activity, and may explain how mutations in the amino-terminal region contribute to the cancer predisposition syndrome TOC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.